Challenges for a broad international implementation of the current severe community-acquired pneumonia guidelines.

Severe community-acquired pneumonia (sCAP) remains one of the leading causes of admission to the intensive care unit, thus consuming a large share of resources and is associated with high mortality rates worldwide. The evidence generated by clinical studies in the last decade was translated into recommendations according to the first published guidelines focusing on severe community-acquired pneumonia. Despite the advances proposed by the present guidelines, several challenges preclude the prompt implementation of these diagnostic and therapeutic measures. The present article discusses the challenges for the broad implementation of the sCAP guidelines and proposes solutions when applicable.

A Randomized, Open-Label, Non-inferiority Clinical Trial Assessing 7 Versus 14 Days of Antimicrobial Therapy for Severe Multidrug-Resistant Gram-Negative Bacterial Infections: The OPTIMISE Trial Protocol.

INTRODUCTION: Shorter courses of antimicrobials have been shown to be non-inferior to longer, "traditional" duration of therapies, including for some severe healthcare-associated infections, with a few exceptions. However, evidence is lacking regarding shorter regimes against severe infections by multidrug-resistant Gram-negative bacteria (MDR-GNB), which are often caused by distinct strains and commonly treated with second-line antimicrobials. In the duratiOn of theraPy in severe infecTIons by MultIdrug-reSistant gram-nEgative bacteria (OPTIMISE) trial, we aim to assess the non-inferiority of 7-day versus 14-day antimicrobial therapy in critically ill patients with severe infections caused by MDR-GNB. METHODS: This is a randomized, multicenter, open-label, parallel controlled trial to assess the non-inferiority of 7-day versus 14-day of adequate antimicrobial therapy for intensive care unit (ICU)-acquired severe infections by MDR-GNB. Adult patients with severe infections by MDR-GNB initiated after 48 h of ICU admission are screened for eligibility. Patients are eligible if they proved to be hemodynamically stable and without fever for at least 48 h on the 7th day of adequate antimicrobial therapy. After consenting, patients are 1:1 randomized to discontinue antimicrobial therapy on the 7th (± 1) day or to continue for a total of 14th (± 1) days. PLANNED OUTCOMES: The primary outcome is treatment failure, defined as death or relapse of infection within 28 days after randomization. Non-inferiority will be achieved if the upper edge of the two-tailed 95% confidence interval of the difference between the clinical failure rate in the 7-day and the 14-day group is not higher than 10%. CONCLUSION: The OPTIMISE trial is the first randomized controlled trial specifically designed to assess the duration of antimicrobial therapy in patients with severe infections by MDR-GNB. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05210387. Registered on 27 January 2022. Seven Versus 14 Days of Antibiotic Therapy for Multidrug-resistant Gram-negative Bacilli Infections (OPTIMISE).

Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. METHODS: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 µg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475. FINDINGS: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. INTERPRETATION: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. FUNDING: The National Institute of Allergy and Infectious Diseases (USA).

Ebola virus disease and the search for a cure

Ebola virus disease (EVD) was first identified in 1976 in Yambuku, Zaire (now the Democratic Republic of Congo), and is caused by an RNA virus in the filovirus family (Feldmann & Geisbert). The current strain circulation in West Africa is very similar to the original strain (>95% homology). The origin of the current outbreak remains unknown, but it is suspected to be from an animal reservoir with intermediary species (Fauci). Randomized clinical trials with adaptive design are ongoing to evaluate potential new therapies for EVD...

An international survey of cytomegalovirus prevention and treatment practices in intestinal transplantation.

BACKGROUND: Practice variation regarding cytomegalovirus (CMV) prevention and treatment across intestinal transplantation (IT) programs is unknown. METHODS: An electronic survey was sent to IT programs registered with the Intestinal Transplant Association. Proportions were analyzed for categorical variables; means and SDs were analyzed for continuous variables. RESULTS: Seventy-seven percent of IT programs responded to the survey. For CMV D+/R- recipients, 39.1% programs used universal prophylaxis (UP), 8.7% preemptive strategy (PE), and 52.2% hybrid strategy. For CMV R+ recipients, 45.8% programs used UP, 12.5% PE, 37.1% hybrid strategy, and 4.2% none. For CMV D-/R- recipients, 39.1% programs used UP, 21.7% PE, 26.1% hybrid strategy, and 13% none. Frequency of monitoring for PE was weekly 71.4% of programs, every 2 weeks 21.4%, and monthly 7.1%. For CMV viremia, syndrome and disease, the most common first-line agents used were ganciclovir (100% and 96.2%) and valganciclovir (23.1%) and the second-line agent was foscarnet (73.1% and 84.6%). Immunoglobulins were administered in 65.4% of the programs for pneumonia (69.2%), meningoencephalitis (50%), enteritis (46.2%), colitis (38.5%), syndrome (42.3%), viremia (30.8%), and resistant/refractory infections (11.5%). CONCLUSIONS: Prophylaxis and hybrid strategy were the most commonly used. Treatment practices were consistent and mainly involved ganciclovir as first-line agent and foscarnet as second-line agent. The use of immunoglobulins appeared to be more common than in other allografts.

Quantitative versus qualitative cultures of respiratory secretions for clinical outcomes in patients with ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia (VAP) is a common infectious disease in intensive care units (ICUs). The best diagnostic approach to resolve this condition remains uncertain. OBJECTIVES: To evaluate whether quantitative cultures of respiratory secretions are effective in reducing mortality in immunocompetent patients with VAP, compared with qualitative cultures. We also considered changes in antibiotic use, length of ICU stay and mechanical ventilation. SEARCH METHODS: We searched The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 2, 2011, which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to June Week 4, 2011), EMBASE (1974 to June 2011) and LILACS (1982 to June 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing respiratory samples processed quantitatively or qualitatively, obtained by invasive or non-invasive methods from immunocompetent patients with VAP and which analysed the impact of these methods on antibiotic use and mortality rates. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and trials identified in the search results and assessed studies for suitability, methodology and quality. We analysed data using Review Manager software. We pooled the included studies to yield the risk ratio (RR) for mortality and antibiotic change with 95% confidence intervals (CI). MAIN RESULTS: Of the 4459 references identified from the electronic databases, five RCTs (1367 patients) met the inclusion criteria. Three studies compared invasive methods using quantitative cultures versus non-invasive methods using qualitative cultures, and were used to answer the main objective of this review. The other two studies compared invasive versus non-invasive methods, both using quantitative cultures. We combined all five studies to compare invasive versus non-invasive interventions for diagnosing VAP. The studies that compared quantitative and qualitative cultures (1240 patients) showed no statistically significant differences in mortality rates (RR 0.91; 95% CI 0.75 to 1.11). The analysis of all five RCTs showed there was no evidence of reduction in mortality in the invasive group versus the non-invasive group (RR 0.93; 95% CI 0.78 to 1.11). There were no significant differences between the interventions with respect to the number of days on mechanical ventilation, length of ICU stay or antibiotic change. AUTHORS' CONCLUSIONS: There is no evidence that the use of quantitative cultures of respiratory secretions results in reduced mortality, reduced time in ICU and on mechanical ventilation, or higher rates of antibiotic change when compared to qualitative cultures in patients with VAP. Similar results were observed when invasive strategies were compared with non-invasive strategies.

Síndrome da distrição respiratória aguda (SDRA) / Acute respiratory distress syndrome

Os autores fazem revisão sobre o diagnósticoe tratamento da Síndrome da Distrição Respiratória aguda